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Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

Positive Regulator Molecules

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.

Positive Regulator Molecules

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.

Negative Regulator Molecules

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.

Anaphase Promoting Complex

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...

Separation of Sister Chromatids

Separation of Sister Chromatids

At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...

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Related Experiment Video

Updated: Nov 6, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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Published on: October 26, 2015

Restraining CDK1-cyclin B activation: PP2A on the cUSP(7).

Marilynn Chow-Castro¹, Shandee D Dixon¹, Joshua C Saldivar^1,2

¹Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

The EMBO Journal

|May 10, 2021

Summary

USP7 inhibitors, used to stabilize p53, cause unexpected toxicity by disrupting cell cycle regulation. This study reveals USP7 inhibition causes PP2A redistribution and CDK1-dependent phosphorylation, impacting genomic integrity.

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Area of Science:

Molecular biology
Cell biology
Cancer therapeutics

Background:

USP7 inhibitors are investigated for cancer therapy by stabilizing p53 via MDM2 degradation.
These inhibitors exhibit p53-independent toxicity through an uncharacterized mechanism.

Purpose of the Study:

To elucidate the mechanism behind p53-independent toxicity induced by USP7 inhibitors.
To identify the role of USP7 inhibition in cellular regulation and its impact on genomic integrity.

Main Methods:

Cellular and molecular biology techniques were employed.
Analysis of protein localization, phosphorylation events, and cell cycle progression.

Main Results:

USP7 inhibition causes a shift of Protein Phosphatase 2A (PP2A) from the cytoplasm to the nucleus.
Increased CDK1-dependent phosphorylation occurs throughout the cell cycle upon USP7 inhibition.
This leads to aberrant progression of S-phase cells into mitosis, compromising genomic integrity.

Conclusions:

USP7 inhibition triggers a novel toxicity pathway involving PP2A redistribution and aberrant cell cycle control.
Understanding this mechanism is crucial for developing safer USP7-targeting cancer therapies.
The findings reveal a new regulatory pathway for cell cycle progression and genomic stability.